The group of organophosphorus cholinesterase inhibitors include certain esters of phosphoric acid derivatives, e.g., nitrostigmine (=diethyl-(4-nitrophenyl)-thiophosphate), better known under the names Parathion or E 605, but they also include tabun, as well as the phosphonic acid derivatives sarin, soman and VX.
Among other things cholinesterase-inhibiting phosphoric esters are used as insecticides in agriculture. Since they have a toxic effect on human beings too, the staff working in agriculture is subject to a basic hazard to life and limb; this is true all the more since these organic phosphoric esters can also be absorbed via the skin. As compared to insecticides, the compounds tabun, sarin, soman and VX which belong to the group of the so-called nerve warfare agents are distinguished by a particularly high toxicity. All of these compounds are more or less strong inhibitors of acetylcholinesterase, an enzyme which physiologically blocks the effect of the transmitter acetylcholine released at certain nerve endings. Most of the symptoms of poisoning caused by cholinesterase inhibitors are produced by an inundation with endogenic acetylcholine.
The basic drug therapy of such a poisoning consists in the administration of the parasympatholytic atropine, blocking the exceeding muscarinic acetylcholine effects (e.g., increase of secretion in the respiratory system, bronchospasm, inhibition of the central nervous respiratory drive). There is no suitable antagonist available to normalize the exceeding nicotinic acetylcholine actions (e.g., inhibition of the impulse transmission at the synapses of motorial nerves to the respiratory musculature and to other skeletal muscles up to a complete peripheral motor paralysis). The peripherally caused myoparesis can only be compensated by oximes, e.g., pralidoxime (PAM) or obidoxime (Toxogonin.RTM.) whose mechanism of action consists in a reactivation of the inhibited acetylcholinesterase.
However, this post-exposure therapy is not sufficient to ensure survival after poisoning with the double LD.sub.50 of soman (LD.sub.50 =dose which is lethal for 50% of the exposed subjects). The probability of survival after a soman poisoning increases only when a pretreatment with a carbamate, e.g., pyridostigmine or physostigmine, has taken place prior to the poison exposure, and when additionally the conventional antidote-therapy with atropine and an oxime is started immediately on occurrence of the first symptoms of the poisoning. The requirement with respect to the carbamate used in the pretreatment is that it should not have significant undesired effects at the highest possible, lasting protective action, in particular it must not impair reaction capacity.
Some of the organophosphorus cholinesterase inhibitors are distinguished by the fact that they split off alkyl residues after accumulation to the acetylcholinesterase, thus stabilizing the bond ("aging"). The aged esterase inhibitor complex cannot be reactivated by oximes. In case of poisonings caused by the nerve warfare agent soman, aging already occurs after 2 to 5 minutes. The therapy with atropine and oximes can considerably be improved by a preliminary treatment with indirect parasympathomimetics, e.g., carbamic acid esters, such as pyridostigmine and physostigmine.
Carbamic acid esters inhibit the acetylcholinesterase in a manner similar to that of phosphoric acids. However, the bond is of a shorter duration and completely reversible. The fact that the carbamates inhibit part of the acetylcholinesterase, if dosed suitably, and thus remove it from the reach of the phosphoric esters and phosphonates having a stronger and prolonged inhibition may well be a decisive factor for their protective action, provided that the pretreatment started in time.
Also, the treatment of poisoning caused by phosphoric insecticides requires prompt medical care in any case. Since medical care in case of harvesters cannot always be accomplished promptly, there is a need for drugs prophylactically counteracting an intoxication. The use of carbamic acid esters for this purpose has already been described (Leadbeater, L. Chem. in Brit. 24, 683, 1988). The same applies to the effectiveness of carbamic acid esters in the pretreatment of a soman poisoning in animal experiments (Fleischer, J. H., Harris, L. W. Biochem. Pharmacol. 14, 641, 1965; Berry, W. K., Davies, D. R. Biochem. Pharmacol. 19, 927, 1970). The effective dosage of drugs to be applied prophylactically should not impair reactivity and functional capacity. However, carbamic acid esters have a low therapeutic index. As compared to pyridostigmine, an increased protective action can be achieved by physostigmine, however, the side effects are more severe.
On principle, undesired parasympathomimetic effects of the carbamates can be repressed by combinations with a parasympatholytic (e.g., atropine, scopolamine).
DE-OS 41 15 558 describes a prophylactic antidote consisting of a combination of pyridostigmine or physostigmine and N-methyl-4-piperidyl-1-phenylcyclopentane carboxylate-hydrochloride or arpenal, sycotrol, carmiphene or benactyzine, and, as an additional compelling component, a tranquilizer, i.e., diazepam or clonazepam. The undesired effects of physostigmine or pyridostigmine can therefore not be suppressed by the mentioned parasympatholytics alone, for this reason tranquilizers are additionally administered, whose side effects are problematic too.
Accordingly, it is necessary to allow the prophylactic administration of carbamic acid esters or other indirect parasympathomimetics at a dosage causing a sufficient protection against organophosphorus cholinesterase inhibitors without undesired accompanying effects.